Some immunological reagents can protect persons and animals from many microbial and viral infections, from toxic incapacitation or death, and from certain noninfectious diseases. In some cases, post-onset treatment of these conditions is possible with these reagents. These immunological reagents are effective only when a proper administration regimen is followed. The proper method of administration often includes multiple sequential exposures to the immunogenic material over a period of weeks or months in order to stimulate an immunological defense. For example, in a classic immunization regimen, a single dose of vaccine, a "primer" is delivered in one injectable or oral dose, producing a short-term immunity. Vaccination is repeated one or more times, with "booster" doses, producing a secondary immune response which gives rise to a long-lasting immunity. The availability of trained medical or veterinary personnel and careful medical record maintenance are required to implement these multiple administrations. Moreover, such multiple administrations may not be logistically feasible for certain groups of people, such as in areas where the population is dispersed, as well as for certain livestock, such as chickens and cattle, where the number of individual animals to be dosed is very large.
Several different approaches have been tried to solve this problem. One approach is to prolong the presence of immunogen in the individual or animal from a single administration, thereby reducing the need for subsequent doses of the immunogen. For injectable vaccines, the length of time that vaccine immunogen is present as a result of one injection can be extended by utilizing an oil based medium such as Freunds' Complete Adjuvant, which degrades and releases antigen slowly. (Freund, J., Am. J. Clin. Pathol. 21:645 (1951)). Because of the degradation products produced, however, this medium is not approved for use in humans. Various synthetic polymers have been used as binders in delivery systems which are capable of sustained release of proteins for prolonged periods. (Langer, R. and Folkman, J., Nature 263:797 (1976); Langer, R. and Preis, I., J. Immunol. Methods 28:193 (1979)). Many of these synthetic polymers, however, are not biodegradable, and thus also have limited use in humans. Other polymers which are biodegradable or bioerodible have been developed as well. (Tice and Gilley, U.S. Pat. No. 4,897,268; Beck, U.S. Pat. No. 4,919,929; Kohn, J., Niemi, S. M., Albert, E. L., Murphy, J. C., Langer, R. and Fox, J. G., J. Immunol. Methods 95:31-38 (1986)). These polymers, however, result in gradual and continuous release of antigen, rather than delayed release, and thus do not provide for the most effective immunization.
Controlled release delivery systems whose object is to produce delayed release of immunogen, have also been described. Wheatly, Langer and Eisen were awarded a patent which involves entrapping the substance to be delivered in liposomes and encapsulating the liposomes in a polymer matrix. The liposomes are either sensitive to specific stimuli such as temperature, pH, or light, or the liposomes contain an enzyme in the matrix which produces delayed release of the substance from the matrix encapsulated liposomes. (U.S. Pat. No. 4,921,757). Such a system is complex. Moreover, the pulsing depends on the integrity of the enzymatic activity. These inventors also describe a system involving formation of ionically-coated microcapsules around the substance to be delivered with a microcapsule core-degrading enzyme, resulting in delayed release of the substance. (U.S. Pat. No. 4,933,185). The above described delivery systems require an encapsulation step wherein the immunogen is encapsulated in a liposome or microcapsule. All such systems which require a shell around an active ingredient suffer from the inherent problem that a flaw in the shell can result in a drastically changed pattern of release.
Beck, Flowers, Cowsar and Tanquary describe antigen containing microparticles for immunization of female reproductive organs designed to produce delayed release of antigen by encapsulating a core of antigen with a shell matrix material. (U.S. Pat. No. 4,756,907). This system is designed to release the antigen, after transport of the microparticles, by disruption of the outer shell of the microparticles by some endogenous factor, e.g., the difference in pH of the mucosal fluids in the vagina as compared to the pH of the cervix and uterus. Such a system can only be utilized in a limited number of situations. There is considerable variation among individuals which restricts the use of such a system. This system also suffers from problems associated with shells. The Beck patent also describes intermittent release of antigen produced by multi-layering degradable polymer and antigen. This system requires the manufacture of a multi-layered device. The manufacturing of such a product is complex, requiring multiple production steps.